Chemical-cross linking combined with proteolytic digestion and mass spectrometry is a promising approach to study protein-protein interactions. The distance constrains of the cross-linker between defined amino acid residues allows structural characterization of protein complexes. The gross three dimensional structure of a protein, contact interface between multi-protein complexes, stoichiometry and configuration of the constituent units of a complex are a few of the pieces of useful information that can be derived from cross-linking based mass spectrometry approaches. However, gas-phase dissociation reactions of protonated cross-linkers lack the sensitivity and specificity required to fragment the cross-linker at the desired location.
There remains a need, therefore, for improved cross-linkers for studying protein interactions. Methods of using improved cross-linkers in mass spectrometry for studying protein interactions are also needed.